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Cited by 13GDF15 and Related BiomarkersBone health and treatmentsProstate Cancer Treatment and Research

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GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment

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Yamamichi, Gaku, Kato, Taigo, Arakawa, Noriaki, Ino, Yoko, Ujike, Takeshi, Nakano, Kosuke, Koh, Yoko, Motoyama, Yuichi, Outani, Hidetatsu, Myoba, Shohei, Ishizuya, Yu, Yamamoto, Yoshiyuki, Hatano, Koji, Kawashima, Atsunari, Fukuhara, Shinichiro, Uemura, Hiroji, Okada, Seiji, Morii, Eiichi, Nonomura, Norio, Uemura, Motohide·2024·Biomarker Research
DOI 10.1186/s40364-024-00695-6PMC PMC11590406

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Abstract

Background: Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC. Methods: We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed. Results: A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2 , OSX , ATF4 , NFATc1 , and DC-STAMP . In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP ( r = 0.63) but not with that of PSA ( r = -0.16). Conclusions: GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

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Metadata

Authors
Yamamichi, G., Kato, T., Arakawa, N., Ino, Y., Ujike, T., Nakano, K., Koh, Y., Motoyama, Y., Outani, H., Myoba, S., Ishizuya, Y., Yamamoto, Y., Hatano, K., Kawashima, A., Fukuhara, S., Uemura, H., Okada, S., Morii, E., Nonomura, N., & Uemura, M.
Affiliations
  • The University of Osaka (JP)
  • National Institute of Health Sciences (JP)
  • Advanced Medical Research Center, Yokohama City University (JP)
  • Tosoh (Japan) (JP)
  • Yokohama City University Medical Center (JP)
  • Fukushima Medical University (JP)
Corresponding author
Kato, Taigo
ORCID
Venue
Biomarker Research
Publisher
Springer Science and Business Media LLC
Published
2024-11-25
Volume
12
Issue
1
Pages
147-147
ISSN
2050-7771 (ISSN-L)
DOI
10.1186/s40364-024-00695-6
PMC
PMC11590406
OpenAlex
W4404673571
Cited by
13
References
3
Citations by year
2026: 7 · 2025: 6
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomarker Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • OUKA (Osaka University Knowledge Archive) (Osaka University) (submittedVersion)
Funders
Japan Society for the Promotion of Science (21K09396, 20K23002 and 24K12436)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
  • Health Sciences › Medicine › Oncology › Bone health and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Keywords
bone metastasis, castration-resistant prostate cancer, blood biomarkers, secretome, bone microenvironment, osteoblasts, osteoclasts, bone formation and resorption, Runx2, ATF4, DC-STAMP, bone scan index, tumor microenvironment

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